Neuropeptide Y (NPY) is an amidated peptide widely distributed in the central and peripheral nervous systems (Tatemoto, et al., Nature 296:659-660 (1982); Ekblad, et al., Regul. Peptides 8:225-235 (1984)). It is present in all sympathetic nerves innervating the cardiovascular system and is the most abundant peptide in the brain and the heart (Tatemoto, et al., Nature 296:659-660 (1982)). In addition, NPY is present in platelets (Ericsson, et al., Proc. Natl. Acad. Sci. U.S.A. 84:5587-5591 (1987)), the endothelium (Id.); the adrenal medulla (Allen, et al., J Auton. Nerv. Sys. 9:559-566 (1983)); the pancreas (Jamal, et al., Endocrinology 129:3372-3380 (1991)); the kidney (Grouzmann, et al., Peptides 15 (8):1377-1382 (1994)); and the pituitary gland (Gehlert, et al., Peptides 15 (4):651-656 (1994)). Peptide YY (PYY) is a closely related peptide that has similar biological effects to NPY and which is found primarily in the gut.
The biological actions of NPY and peptide YY are mediated by a number of G-protein coupled receptors termed Y1, Y2, Y3, Y4/PP and Y5 (Herzog, et al., Proc. Natl. Acad. Sci. U.S.A. 89:5794-5798 (1992)). Of these, the physiological effects associated with the Y1 and Y2 receptors are the best characterized. Exposure to a Y1 agonist causes an increase in blood pressure and potentiates post-synaptically the action of other vasoactive substances (Wahlestedt, et al., J. Pharmacol. Exp. Ther. 234:735-741 (1985)). In contrast, Y2 receptors are mainly located presynaptically and, upon stimulation, mediate the inhibition of neurotransmitter release (Westfall, et al., J. Cardiovasc. Pharmacol. 10:716-722 (1987)).
NPY has a number of biological effects of potential therapeutic importance. Intranasal administration of NPY reduces nasal airway resistance and vascular permeability without affecting submucosal gland secretion (Baraniuk, et al., Am. J. Respir. Cell. Mol. Biol. 3:165-173 (1990); Baraniuk, et al., J. Appl. Physiol. 73 (5):1867-72 (1992)). In healthy volunteers, intranasal pretreatment with exogenous NPY markedly reduces vasodilation and nasal secretion induced by afferent nerve stimulation with capsaicin or histamine (Lacroix, et al, Br. J. Pharmacol. 118:2079-2084 (1996)). Therapeutic application of NPY in the treatment of rhinitis has been recently suggested since allergen-evoked nasal responses in patients are significantly attenuated after local pretreatment with the peptide (Lacroix, et al., J. Allergy Clin. Immunol. 98:611-616 (1996)).
NPY also plays an important role in modulating the cardiovascular system, behavior, anxiety and the secretion of certain hormones (Wahlestedt, et al., Annu. Rev. Pharmacol. Toxicol. 33:309-352 (1993); Michel, Trends Pharmacol. Sci. 12:389-394 (1991)). It contributes to the central and peripheral control of blood pressure, the regulation of feeding behavior, obesity, diabetes and psychiatric disorders (Walker, et al., Trends Pharmacol Sci 12:111-115 (1991); Sahu, et al., Trends Endocrinol. Metab. 4:217-224 (1993); Stanley, et al., Proc. Natl Acad. Sci. USA 82:3940-3943 (1985)).